UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity

Zhong,Jialing; Zhao,Mei; Ma,Yiming; Luo,Qing; Liu,Jian; Wang,Jia; Yuan,Xinghua; Sang,Jianli; Huang,Changzhi

doi:10.3892/ijmm.2012.1012

UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity

Authors:
- Jialing Zhong
- Mei Zhao
- Yiming Ma
- Qing Luo
- Jian Liu
- Jia Wang
- Xinghua Yuan
- Jianli Sang
- Changzhi Huang
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Affiliations: Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China, Department of Abdomen Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, P.R. China
Published online on: May 25, 2012 https://doi.org/10.3892/ijmm.2012.1012
Pages: 430-436

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Abstract

Ubiquitin C-terminal hydrolase-L1 (UCHL1) belongs to the family of deubiquitinating enzymes (DUBs), which is involved in the ubiquitin-dependent proteolytic system. Previously, we have reported that the upregulation of UCHL1 is related to lymph node metastasis in colorectal cancer (CRC). However, its molecular mechanisms remain elusive. In this study, we transfected pcDNA3.1/UCHL1 and the pcDNA3.1/UCHL1-C90S mutant into HCT8 cells. The changes in biological features in these stable transfectants were examined both in vitro and in vivo. Western blot analysis was used to analyze the changes in the β-catenin/T cell factor (TCF) pathway. We demonstrated that UCHL1 re-expression promoted the proliferation, migration and metastasis potential of HCT8 cells both in vitro and in vivo. We also found that UCHL1 could decelerate β-catenin degradation depending on its deubiquitinating activity. The accumulated β-catenin consequently activated the β-catenin/TCF pathway and induced the expression of cyclin D1 and uPA. These observations imply that UCHL1 may contribute to CRC progression by activating the β-catenin/TCF pathway through its deubiquitinating activity.

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1.	DM ParkinF BrayJ FerlayP PisaniGlobal cancer statistics, 2002CA Cancer J Clin5574108200510.3322/canjclin.55.2.74
2.	B LevinP BoyleWorld cancer report 2008International Agency for Research on CancerLyon3743792008
3.	H OsakaYL WangK TakadaS TakizawaR SetsuieH LiY SatoK NishikawaYJ SunM SakuraiUbiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuronHum Mol Genet1219451958200310.1093/hmg/ddg21112913066
4.	R SetsuieK WadaThe functions of UCH-L1 and its relation to neurodegenerative diseasesNeurochem Int51105111200710.1016/j.neuint.2007.05.00717586089
5.	HJ KimYM KimS LimYK NamJ JeongHJ KimKJ LeeUbiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasisOncogene28117127200910.1038/onc.2008.36418820707
6.	A LeiblichSS CrossJW CattoG PesceFC HamdyI RehmanHuman prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin AProstate6717611769200710.1002/pros.2065417929277
7.	E TezelK HibiT NagasakaA NakaoPGP9.5 as a prognostic factor in pancreatic cancerClin Cancer Res6476447672000
8.	L LiQ TaoH JinA van HasseltFF PoonX WangMS ZengWH JiaYX ZengAT ChanY CaoThe tumor suppressor UCHL1 forms a complex with p53/MDM2/ARF to promote p53 signaling and is frequently silenced in nasopharyngeal carcinomaClin Cancer Res1629492958201010.1158/1078-0432.CCR-09-317820395212
9.	E Okochi-TakadaK NakazawaM WakabayashiA MoriS IchimuraT YasugiT UshijimaSilencing of the UCHL1 gene in human colorectal and ovarian cancersInt J Cancer11913381344200610.1002/ijc.2202516642472
10.	J YuQ TaoKF CheungH JinFF PoonX WangH LiYY ChengC RöckenMP EbertEpigenetic identification of ubiquitin carboxyl-terminal hydrolase L1 as a functional tumor suppressor and biomarker for hepatocellular carcinoma and other digestive tumorsHepatology48508518200810.1002/hep.22343
11.	DL MandelkerK YamashitaY TokumaruK MimoriDL HowardY TanakaAL CarvalhoWW JiangHL ParkMS KimPGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinomaCancer Res6549634968200510.1158/0008-5472.CAN-04-392315930319
12.	Y MiyoshiS NakayamaY TorikoshiS TanakaH IshiharaT TaguchiY TamakiS NoguchiHigh expression of ubiquitin carboxy-terminal hydrolase-L1 and -L3 mRNA predicts early recurrence in patients with invasive breast cancerCancer Sci97523529200610.1111/j.1349-7006.2006.00202.x16734731
13.	T TakaseK HibiT YamazakiH NakayamaM TaguchiY KasaiK ItoS AkiyamaT NagasakaA NakaoPGP9.5 overexpression in esophageal squamous cell carcinomaHepatogastroenterology5012781280200314571718
14.	WJ WangQQ LiJD XuXX CaoHX LiF TangQ ChenJM YangZD XuXP LiuOverexpression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancercellsInt J Oncol3310371045200818949367
15.	T YamazakiK HibiT TakaseE TezelH NakayamaY KasaiK ItoS AkiyamaT NagasakaA NakaoPGP9.5 as a marker for invasive colorectal cancerClin Cancer Res8192195200211801558
16.	Y MaM ZhaoJ ZhongL ShiQ LuoJ LiuJ WangX YuanC HuangProteomic profiling of proteins associated with lymph node metastasis in colorectal cancerJ Cell Biochem11015121519201010.1002/jcb.2272620524204
17.	CN LarsenJS PriceKD WilkinsonSubstrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active siteresiduesBiochemistry3567356744199610.1021/bi960099f8639624
18.	E HiendlmeyerS RegusS WassermannF HlubekA HaynlA DimmlerC KochC KnollM van BeestU ReuningBeta-catenin upregulates the expression of the urokinase plasminogen activator in human colorectal tumorsCancer Res6412091214200410.1158/0008-5472.CAN-3627-214973118
19.	M ShtutmanJ ZhurinskyI SimchaC AlbaneseM D'AmicoR PestellA Ben-Ze'evThe cyclin D1 gene is a target of the β-catenin/LEF-1 pathwayProc Natl Acad Sci USA96552255271999
20.	S FukutomiN SekiK KodaM MiyazakiIdentification of methylation-silenced genes in colorectal cancer cell lines genomic screening using oligonucleotide arraysScand J Gastroenterol4214861494200710.1080/00365520701491173
21.	Y Akishima-FukasawaY InoY NakanishiA MiuraY MoriyaT KondoY KanaiS HirohashiSignificance of PGP9.5 expression in cancer-associated fibroblasts for prognosis of colorectal carcinomaAm J Clin Pathol1347179201010.1309/AJCPRJP39MIDSGBH20551269
22.	Y HongKS HoKW EuPY CheahA susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathway: implication for tumorigenesisClin Cancer Res1311071114200710.1158/1078-0432.CCR-06-163317317818
23.	H MizukamiA ShirahataT GotoM SakataM SaitoK IshibashiG KigawaH NemotoY SanadaK HibiPGP9.5 methylation as a marker for metastatic colorectal cancerAnticancer Res2826972700200819035297
24.	M BienzH CleversLinking colorectal cancer to Wnt signalingCell103311320200010.1016/S0092-8674(00)00122-711057903
25.	A BhedaW YueA GullapalliC WhitehurstR LiuJS PaganoJ ShackelfordPositive reciprocal regulation of ubiquitin C-terminal hydrolase L1 and beta-catenin/TCF signalingPLoS One4e5955200910.1371/journal.pone.000595519536331
26.	CJ SherrCancer cell cyclesScience27416721677199610.1126/science.274.5293.16728939849
27.	S MazaudR GuyotCJ GuigonN CoudouelB Le Magueresse-BattistoniS MagreBasal membrane remodeling during follicle histogenesis in the rat ovary: contribution of proteinases of the MMP and PA familiesDev Biol277403416200510.1016/j.ydbio.2004.10.00115617683
28.	H MorganPA HillHuman breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activityCancer Cell Int51200510.1186/1475-2867-5-1